Summary Salivary gland dysfunction affects millions of Americans whose quality of life is severely impacted by dry mouth, oral bacterial infections, poor nutrition and other disorders associated with decreased saliva production. Loss of saliva is symptomatic of Sjgren's syndrome (SS), an autoimmune disease associated with lymphocytic infiltration of the salivary gland, autoantibody production and ultimately tissue degeneration. A commonality between many human autoimmune diseases, including SS, is chronic inflammation whereby sustained accumulation of immune cells promotes tissue degeneration and often leads to other damaging effects including tissue fibrosis, secondary autoimmune diseases (e.g. lupus, rheumatoid arthritis) and the development of lymphoma. A major focus of this proposal is to identify the functional relevance of ?alarmones? that are produced at the site of initial tissue damage and the cellular mechanisms whereby alarmones mobilize the systemic immune system leading to chronic inflammation. Among possible alarmones that initiate autoimmune disease in salivary glands, our laboratory has investigated the effect of localized release of nucleotides, such as ATP, from damaged cells or tissues. We have shown that G protein-coupled P2Y2 receptors (P2Y2R) for ATP and UTP are early responders to released nucleotide alarmones and that knockout of the P2Y2R in a mouse model of SS prevents infiltration of B and T lymphocytes into salivary glands, indicating a loss of the systemic immune response. We hypothesize that chronic inflammation occurs through P2Y2R activation in SS salivary glands, which increases localized chemokine/cytokine levels and attracts peripheral lymphocyte infiltration across the vascular endothelium into salivary glands. Specific Aims will fully investigate the cell-specific mechanisms that initiate chronic inflammation at the level of P2Y2 receptors in the salivary gland of SS mouse models and test the potential of targeting the P2Y2R in SS mouse models to prevent a systemic immune response. Specific Aim 1 will address the hypothesis that P2Y2R activation in B and T cells promotes their infiltration and proliferation in salivary glands of SS mouse models thereby contributing to salivary gland dysfunction. Specific Aim 2 will address the hypothesis that P2Y2R upregulation in salivary epithelium and vascular endothelium contributes to the autoimmune phenotype in SS mouse models. Specific Aim 3 will evaluate the hypothesis that pharmacological antagonism of P2Y2Rs in vivo reduces chronic inflammation of the salivary glands in two distinct SS mouse models. Successful completion of this project would expedite human studies to target modulation of the P2Y2R in SS to prevent loss of salivary gland function.